Polarisation transfer via a second metal complex

Abstract

There is described a method for preparation of an imaging medium via transfer from a hyperpolarised singlet state that is not parahydrogen, said method comprising the steps of: (i) preparing a system containing: parahydrogen; a magnetisation transfer complex, with a molecular symmetry that allows the creation of a singlet state between spin pairs within it, said complex including a reversibly bound small molecule transference substrate; applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate; (ii) introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised.

The invention claimed is: 
     
       1. A method for the preparation of an imaging medium via transfer from a hyperpolarised singlet state that is not parahydrogen, said method comprising the steps of:
 (i) preparing a system containing: 
 parahydrogen; a magnetisation transfer complex, with a molecular symmetry that allows the creation of a singlet state between spin pairs within it, the magnetization transfer complex including a reversibly bound small molecule transference substrate; 
 applying a magnetic field such that hyperpolarisation is transferred into the magnetization transfer complex, including the reversibly bound small molecule transference substrate; 
 (ii) separately or simultaneously introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised; and 
 (iii) providing an imaging medium by:
 (a) separating the hyperpolarised recipient complex; 
 (b) separating the hyperpolarised recipient substrate; or 
 (c) separating the bound small molecule transference substrate. 
 
 
     
     
       2. A method according to  claim 1  wherein the hyperpolarisation is achieved by SABRE. 
     
     
       3. A method according to  claim 1  wherein the small molecule transference substrate is characterised by a long lifetime in a low magnetic field. 
     
     
       4. A method according to  claim 1  wherein the small molecule transference substrate has a singlet state lifetime that will be 20 seconds or more. 
     
     
       5. A method according to  claim 2  wherein the method includes the use of a SABRE hyperpolarisation transfer catalyst. 
     
     
       6. A method according to  claim 5  wherein a SABRE hyperpolarisation transfer catalyst is placed in an aqueous phase. 
     
     
       7. A method according to  claim 1  wherein parahydrogen (p-H 2 ) gas is added to the system whilst agitating the system. 
     
     
       8. A method according to  claim 7  wherein ultrasound is used to agitate the system. 
     
     
       9. A method according to  claim 1  wherein the recipient complex contains appropriate  2 H, Cl or O labels to maximise the relaxation times of the nuclei spins that are to be hyperpolarised. 
     
     
       10. A method according to  claim 1  wherein the small molecule transference substrate contains appropriate  13 C or  15 N labelling to maximise the proportion of the substrate that can be created in a hyperpolarised NMR visible form in conjunction with appropriate  2 H, O or Cl labelling to extend their magnetic state lifetimes. 
     
     
       11. A method according to  claim 1  wherein the selected small molecule transference substrate contains spin pairs of appropriate  1 H,  13 C,  31 P,  15 N,  29 Si or  19 F labels to enable the formation of long-lived states between corresponding spin pairs within a molecular scaffold that contains appropriate  2 H or Cl labelling to extend their lifetime. 
     
     
       12. A method according to  claim 1  wherein the small molecule transference substrate contains spin pairs that are homo-nuclear. 
     
     
       13. A method according to  claim 1  wherein the small molecule transference substrate contains spin pairs that are selected from  1 H/ 1 H and  13 C/ 13 C. 
     
     
       14. A method according to  claim 1  wherein the small molecule transference substrate contains spin pairs that are hetero-nuclear. 
     
     
       15. A method according to  claim 6  wherein the hyperpolarisation transfer catalyst is provided with at least one suitable ligation site enabling it to interact with one or more small molecule transference substrates. 
     
     
       16. A method according to  claim 15  wherein the hyperpolarisation transfer catalyst comprises an iridium based catalyst. 
     
     
       17. A method according to  claim 6  wherein the hyperpolarization transfer catalyst includes iridium with at least one N-heterocyclic carbene (NHC) ligand. 
     
     
       18. A method according to  claim 17  wherein the N-heterocyclic carbene (NHC) ligand is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       19. A method according to  claim 1  wherein the small molecule transference substrate is selected from one or more of pyridine (py), pyridazine (pdz), methyl-pyridazine (methyl-pdz), d 2 -nicotinate (nic) and Cl 2 -d 2 - 15 N 2 -pyridazine. 
     
     
       20. A method according to  claim 1  wherein a biphasic element is introduced in order to enable the hyperpolarisation transfer process to be completed in a single vessel. 
     
     
       21. A method according to  claim 1  wherein the recipient substrate is selected from the group consisting of nicotinamide, nicotine, pyrazine, 5-methyl pyrimidine, acetate, pyruvate, ethoxide, hydroxide, oxalate or gluconate, sugars, glucose, fructose, urea, amides, amino acids, glutamate, glycine, cysteine, aspartate, GABA (y-aminobutyric acid), nucleotides, vitamins, ascorbic acid, serotonin, penicillin derivatives and sulfonamides. 
     
     
       22. A method of producing a hyperpolarised target substrate imaging medium, said method comprising the steps of:
 (i) preparing a system containing a magnetisation transfer complex, said complex including a reversibly bound small molecule transference substrate; 
 (ii) adding H 2  or parahydrogen (p-H 2 ) gas to the system; 
 (iii) applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate; 
 (iv) separately or simultaneously introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised; and 
 (v) separating the hyperpolarised recipient complex; the hyperpolarised recipient substrate; or the separating the transference substrate to provide a hyperpolarised target substrate imaging medium.